Comparative analysis of coronavirus genomic RNA structure reveals conservation in SARS-like coronaviruses

  1. Wes Sanders
  2. Ethan J. Fritch
  3. Emily A. Madden
  4. Rachel L. Graham
  5. Heather A. Vincent
  6. Mark T. Heise
  7. Ralph S. Baric
  8. Nathaniel J. Moorman

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Abstract

Coronaviruses, including SARS-CoV-2 the etiological agent of COVID-19 disease, have caused multiple epidemic and pandemic outbreaks in the past 20 years 1–3 . With no vaccines, and only recently developed antiviral therapeutics, we are ill equipped to handle coronavirus outbreaks 4 . A better understanding of the molecular mechanisms that regulate coronavirus replication and pathogenesis is needed to guide the development of new antiviral therapeutics and vaccines. RNA secondary structures play critical roles in multiple aspects of coronavirus replication, but the extent and conservation of RNA secondary structure across coronavirus genomes is unknown 5 . Here, we define highly structured RNA regions throughout the MERS-CoV, SARS-CoV, and SARS-CoV-2 genomes. We find that highly stable RNA structures are pervasive throughout coronavirus genomes, and are conserved between the SARS-like CoV. Our data suggests that selective pressure helps preserve RNA secondary structure in coronavirus genomes, suggesting that these structures may play important roles in virus replication and pathogenesis. Thus, disruption of conserved RNA secondary structures could be a novel strategy for the generation of attenuated SARS-CoV-2 vaccines for use against the current COVID-19 pandemic.

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    SciScore for 10.1101/2020.06.15.153197: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Vero-81 cells were cultured to ~80% confluence in T175 flasks.
    Vero-81
    suggested: None
    Vero E6 cells were culture to ~90% confluence in T175 flasks.
    Vero E6
    suggested: None
    Software and Algorithms
    SentencesResources
    SHAPE reactivities were derived using the ShapeMapper Pipeline v1.2.
    ShapeMapper Pipeline
    suggested: None
    All available MERS-CoV (350 genomes), SARS-CoV (140 genomes), and SARS-CoV-2 (1,524 genomes) sequences available on ViPR on 5-12-2020 were searched for similar structures using cmsearch with -A option to automatically generate an alignment.
    ViPR
    suggested: (vipR, RRID:SCR_010685)
    Base pairs with significant covariance were identified using R-scape program v1.2.36.
    R-scape
    suggested: None
    MUSCLE alignments were performed on the CLC Genomics Workbench v12.0.3 (Qiagen) module Additional Alignments v1.9 for mutational frequency identification using the above mentioned ViPR sequences.
    MUSCLE
    suggested: (MUSCLE, RRID:SCR_011812)
    ClustalOmega alignments were performed using EMBL-EBI for individual viral genome comparisons7.
    ClustalOmega
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.06.15.153197v1 on bioRxiv